Endurance training in animal models drove coupled electrical, structural, and inflammatory pulmonary vein-left atrial remodelling, increasing AF inducibility and providing both trigger and substrate.
Does endurance training remodel pulmonary vein sleeve myocytes and promote a proarrhythmic atrial substrate?
Endurance training drives coupled electrical, structural, and inflammatory remodeling in the pulmonary veins, providing a mechanistic explanation for the increased risk of atrial fibrillation in athletes.
Background and AimsThe risk of atrial fibrillation (AF) is higher in endurance athletes. Pulmonary vein isolation (PVI) is effective in this group, implicating pulmonary vein (PV) remodelling, but underlying mechanisms are unclear. This study investigated if endurance training remodels PV sleeves and the PV–left atrial (LA) junction to promote PV triggers and a permissive peri-antral substrate for AF.MethodsIn canine and murine endurance-running models, in vivo PV–LA mapping, ex vivo PV electrophysiology, intracellular action potential (AP) profiling with machine learning classification, histology, bulk RNA-seq, and subcellular-resolution spatial transcriptomics of PV–LA tissue were performed. These findings were incorporated into biophysically detailed computer models of human PV cardiomyocytes and a 3D human LA.ResultsTraining produced an athlete’s heart phenotype and increased AF inducibility. In vivo, trained animals showed PV–LA conduction slowing and increased rotational activity. Ex vivo, trained PVs showed enhanced β-adrenergically evoked firing, prolonged burst activity, and a higher proportion of pacemaker-like APs. Spatial transcriptomics revealed discrete PV myocyte subpopulations with training upregulated Hcn4, Cacna1d, and Cacna1g (enhancing automaticity), downregulated Scn5a and Gja1 (slowing conduction), and enriched profibrotic/inflammatory signalling (Tnfα, Il6) alongside fibroblast expansion and extracellular matrix deposition. In silico, these changes reproduced faster spontaneous PV firing and sustained re-entry.ConclusionsEndurance training drives coupled electrical, structural, and inflammatory PV–LA remodelling that provides both trigger and substrate for AF. These data support why PV-targeted strategies can be effective in athletic AF and nominate modifiable pathways including HCN4-linked automaticity and TNFα-associated signalling.
Luca et al. (2026) studied Atrial fibrillation. Endurance training was evaluated on PV-LA remodelling and AF inducibility. Endurance training in animal models drove coupled electrical, structural, and inflammatory pulmonary vein-left atrial remodelling, increasing AF inducibility and providing both trigger and substrate.